November 15, 2003 | A CURIOUS IRONY: The owner of the Portland Trail Blazers, one of the most dysfunctional teams in professional basketball, chooses to bankroll a $100-million institute for brain research that aims to compile a meticulously detailed 3-D genetic atlas of the brain?

Mark Boguski, founding director of the Allen Institute for Brain Science (AIBS) in Seattle, explains that Paul Allen, the co-founder of Microsoft and multibillionaire, "is a technologist and visionary who has always been interested in science and its applications." And much more besides: Through his investment company Vulcan Inc. and numerous foundations, Allen's resume includes producer of PBS' "The Blues" series, DreamWorks SKG stakeholder, and owner of the Seattle Seahawks. AIBS co-founder Jody Patton is Allen's sister and president/CEO of Vulcan.

During the past few years, according to Boguski, Allen has grown increasingly fascinated with the Human Genome Project and brain research. In the summer of 2001, he convened a brainstorming session with a dozen experts, including Boguski, to explore the possibility of combining the two fields. Two principle ideas emerged: One was to found a research institute to draw connections "from molecules to mind," Boguski says, "including cell biology, neurobiology, psychology, and everything in between."

Brain power: Mouse in situ.

B ut Allen also sought a project that could have a more immediate impact. The result is the Allen Brain Atlas. This flagship project is a high-throughput program that suits Boguski's talents perfectly. "My background in bioinformatics, genomics, and experience in biotech management [at Rosetta Inpharmatics] were probably more important in a startup phase than an intricate knowledge of neuroscience," he says, though he is quick to point out that he did take all the requisite psychology and neurobiology courses during his medical training at Washington University in St. Louis.

Boguski says the institute will boast "a hybrid culture of a Big Biology project with genome center efficiency, but in parallel to that will be more traditional research programs. The findings from the Brain Atlas will seed a variety of programs." The staff will grow to about 75 people in two to three years, with the institute's research agenda guided by a stellar advisory board chaired by Marc Tessier-Lavigne, Stanford neurobiologist and co-founder of Renovis, a biotech devoted to neurological disorders.

Decade of the Brain II
While the 1990s were officially the "Decade of the Brain," Boguski spent that period at the National Center for Biotechnology Information helping establish the field of bioinformatics, playing a key role in creating the computational infrastructure that underpinned the final genome sequence. He moved to Seattle in 2000, joining Rosetta Inpharmatics, only to leave shortly after the company was acquired by Merck in 2001. Most recently, he was a visiting investigator at the Fred Hutchinson Cancer Research Center, building its bioinformatics and genomics programs.

"The Human Genome Project produced linear information," Boguski says. "This is a 3-D project. What do you do after the genome project? What system [other than the brain] could be more challenging?" A primary goal is to use gene-expression patterns to define the geographic boundaries of the brain, an area so rife with disagreement among neuroanatomists that Boguski likens it to comparing maps of Europe before and after World War I. "In the brain, anatomy is everything," he says.

But the challenge is enormous: The brain contains 1 trillion neurons, each cell typically making 1,000 synaptic connections with its neighbors. To manage the task, the AIBS will rely heavily on existing technologies, albeit expanded and resourced to a scale not seen before. This is important, Boguski says, because "you can't rely on completely novel technologies and still get the project done in a few years. Our strategy was to identify best-of-breed technologies applied to this problem, and collect them under one roof, with some outside collaborations."

Although scientists have mapped maybe a few hundred genes in the brain, that is merely 1 percent of the estimated 20,000 genes expressed in the brain. The Brain Atlas aims to produce a comprehensive, quantitative, 3-D map of those genes — achieving cellular resolution with 3-D anatomic fidelity.

"One of the important attributes for the success of this project is use of off-the-shelf technology, but deployed on a large scale," Boguski says. The primary technology will be high-throughput in situ hybridization (HITISH), developed by Swiss biochemist Gregor Eichele, professor at the Baylor College of Medicine. Eichele is helping to set up a production system at the institute based on his GenePaint technology — commercially available from Tecan Group — which removes much of the tedious manual preparation required for in situ hybridization. The first results from this approach — a gene-expression atlas of mouse counterparts to 160 human genes in developing mouse embryos — were published last year (Reymond et al. Nature 420, 582-586; 2002).

Generating expression data is one thing, but storing and extrapolating them into three dimensions is quite another. "We could be approaching 100 terabytes of data per year ... and the total data could hit petabyte range." Boguski is holding active discussions with "certain IT companies about collaborations and potential sponsorship," though he is not ready to name names.

The AIBS could have been developed as a commercial biotech venture, but "Allen wanted this to be a philanthropic endeavor. He wants to have as broad an impact as possible." Allen also seems intent to play a keen role in the institute's growth, and has been known to ask his institute director questions such as, "What is the role of alternative splicing in neurodevelopment?"

With the two dominant biological scientific disciplines of the 1990s — neuroscience and genomics — set to converge as never before, Allen is truly blazing a trail.